Donor Lymphocyte Infusion for Blood Cancers

Overseen by Christopher G Kanakry, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Active non-hematopoietic malignancy, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing if giving white blood cells from a donor to patients with high-risk blood cancers can reduce the risk of the cancer coming back. The goal is to see if this approach helps fight off remaining cancer cells and prevents relapse.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any other investigational drugs, and prior experimental treatments must be completed at least 3 weeks before starting the trial.

What data supports the effectiveness of the treatment Donor Lymphocyte Infusion for Blood Cancers?

Research shows that using busulfan and fludarabine together as part of a conditioning regimen before stem cell transplantation is effective for treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with a high complete remission rate and reduced toxicity. ^{1 2 3 4 5}

Is Donor Lymphocyte Infusion and related treatments generally safe for humans?

Research shows that using fludarabine with busulfan in treatments like stem cell transplants tends to have fewer side effects compared to using cyclophosphamide with busulfan. This combination is associated with lower rates of lung injury, liver problems, and certain infections, suggesting it is generally safer. ^{2 4 6 7 8}

How is the drug combination of Busulfan, Cyclophosphamide, and Fludarabine unique for treating blood cancers?

This drug combination is unique because it uses fludarabine as a less toxic substitute for cyclophosphamide in the standard regimen, potentially reducing side effects while maintaining effectiveness in preparing patients for stem cell transplantation. ^{1 2 4 5 6}

Research Team

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-65 with high-risk blood cancers like leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that are hard to treat or likely to come back. They need a healthy relative who can donate bone marrow and white blood cells for the study.

Inclusion Criteria

I have a donor who matches my HLA type.

I can care for myself but may need occasional help.

My related donor is over 12, willing, and able to donate blood, bone marrow, and stool for research.

Exclusion Criteria

I have not undergone intense bone marrow preparation for stem cell transplant.

I do not have any severe illnesses that would make a transplant risky for me.

Recipient must not be actively breastfeeding

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for various exams and tests

Pre-Transplant Conditioning

Participants receive chemotherapy and other drugs starting 6 days before transplant

1 week

Inpatient stay at NIH hospital

Transplantation

Participants undergo allogeneic hematopoietic cell transplantation

1 day

Inpatient procedure

Donor Lymphocyte Infusion (DLI)

Participants receive donor lymphocyte infusion 7 days post-transplant

1 day

Inpatient procedure

Post-Transplant Monitoring

Participants are monitored for development of GVHD and other outcomes

100 days

Frequent follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic follow-up visits

Treatment Details

Interventions

• Busulfan (Alkylating agents)
• Cyclophosphamide (Alkylating agents)
• Donor Lymphocyte Infusion (Immunotherapy)
• Fludarabine (Antimetabolites)
• Mycophenolate mofetil (Immunosuppressant)
• Sirolimus (mTOR Inhibitor)

Trial Overview The trial is testing if giving patients donor lymphocytes (white blood cells) from their transplant donor soon after a bone marrow transplant can lower the chance of cancer coming back. It includes chemotherapy drugs and staying near NIH for monitoring.

Participant Groups

Group I: Phase II Efficacy, Cohort 2 (haploidentical) Experimental Treatment 6 Interventions

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Group II: Phase II Efficacy, Cohort 1 (matched) Experimental Treatment 6 Interventions

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Group III: Phase I Dose Escalation, Cohort 2 (haploidentical) Experimental Treatment 6 Interventions

DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Group IV: Phase I Dose Escalation, Cohort 1 (matched) Experimental Treatment 6 Interventions

DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Group V: Donor Arm Active Control 1 Intervention

Donors for Recipients in Arms 1-4

Busulfan is already approved in Canada, Japan for the following indications:

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

A population pharmacokinetic/pharmacodynamic model was developed using data from 41 hematopoietic cell transplant recipients to understand how different concentrations of F-ara-A affect lymphocyte suppression.

The model successfully characterized the variability in absolute lymphocyte counts during treatment, indicating that the specific HCT protocol significantly influenced lymphocyte kill rates and could help optimize future fludarabine-based conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. McCune, JS., Vicini, P., Salinger, DH., et al.[2021]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

The combination of intravenous busulfan and fludarabine as a conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) demonstrated a high complete remission rate of 85% in patients with active disease.

This regimen showed low regimen-related (1%) and treatment-related (3%) mortality rates, indicating improved safety, while achieving a 1-year overall survival rate of 65% and event-free survival rate of 52% for all patients, suggesting it is an effective and reduced-toxicity option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. de Lima, M., Couriel, D., Thall, PF., et al.[2021]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

In a study of 42 patients undergoing allogeneic hematopoietic stem cell transplantation, the combination of busulfan and fludarabine (BuFlu) resulted in significantly lower rates of mucositis compared to the traditional busulfan and cyclophosphamide (BuCy) regimen.

Both BuFlu and BuCy showed similar efficacy in terms of engraftment time, relapse risk, event-free survival, and overall survival, suggesting that BuFlu is a viable alternative to BuCy for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. Lee, JH., Choi, J., Kwon, KA., et al.[2021]

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

In a study of 26 patients undergoing hematopoietic stem cell transplantation, those receiving fludarabine showed a significant reduction in the clearance of orally administered busulfan, indicating that fludarabine affects how the body processes busulfan.

Despite higher plasma levels of busulfan in patients treated with fludarabine, these patients experienced less myelosuppression-related toxicity, suggesting that lower doses of busulfan (about 30% less) may be safer and more effective when used with fludarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation. de Castro, FA., Lanchote, VL., Voltarelli, JC., et al.[2013]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. [2021]

2. England pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. [2014]

5. England pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. [2014]

8. England pubmed.ncbi.nlm.nih.gov

Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation. [2013]